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Multivariateanalysisofcomplexphenotypes
Complex->multifactorialtraitsPhenotype->categorical&quantitativefeatures
Analysis->association&modeling
NGS(Comprehensiveevaluationallgenevariants)GWAS(mainlycommonallele,MAF>0.05)
Univariategeneassociationanalysis
Distributedriskassociatedloci (regulatoryvariants) Raredamaginglossoffunctionmutations(functionalvariants)
Multifactorialassociations
Marginaladditiveeffect ofseveralvariants Thephenotypedependsongenotypecombinations
Checkforthepresenceofinteractionsdeviatingfromapureadditivebehavior
POLYGENICRISKSCORE EPISTASIS
Epistasis analysis reveals associations between gene variants and bipolar disorder
Twocomputational/statisticalissues:
• Curseofdimensionality
• Lowstatisticalpowerfollowingmultipletestadjustment
Imputation(commonalleles)basedonreferencehaplotypes
GenotypesSNPs Haplotypereference Boostedsignal
Genotypematrix(incomparisontoreference) Eachsampleisa
mosaicofhaplotypes
Imputedgenotypematrix
GenotypesSNPs Haplotypereference Boostedsignal
Genotypematrix(incomparisontoreference) Eachsampleisa
mosaicofhaplotypes
Imputedgenotypematrix
HaplotypePhasing
• Allowcross-platformscomparison:1. Meta-analysis2. PRSdifferentGWAS
Minimac3
PRSanalysisandlogistic/linearregression
Case/controlGivenabaseassociationandtargetgenotype(afterimputation)
• IdentifycommonSNPs
• Clumptofilterforindependentsignal
• ComputePRSoverarangeofp-valuethreshold
• Identifybestfittingmodel
Permutationsarepossibletocorrectformultipletesting(nonindependenttest)
Metabolicdata:matrixoflevelsinblood
Commonpolygenicvariationcontributestoriskofschizophreniaandbipolardisorder(PMID19571811)
RESULTS:
• Thereisanadditivepolygeniccomponentinpsychiatricphenotypes
• Thereisasharedgeneticscomponentbetweenschizophreniaandbipolardisorder
• Thereisnorelevantoverlapbetweenthegeneticscomponentofschizophreniaandnon-psychiatrydiseases
• TheeffectismainlyduetoSNPsinannotatedgeneregions(ratherthanintergenicregions)
WhatwecanlearnfromPRS
CommonpolygenicvariationenhancesriskpredictionforAlzheimer'sdisease. PMID26490334
PRSandprediction
Arapidmethodforcombinedanalysisofcommonandrarevariantsatthelevelofaregion,gene,orpathwayPMID22888262
PRSincludingrarevariants
StandardPRS Weighbasedonallelefrequency
Weigh/frequencyrelationParabola(minimumatq=0.5,f=intercept) Screenoverdifferentfvalues
Accumulationofminorallelesandriskpredictioninschizophrenia PMID:28916820
PathwayspecificPRS
DisproportionateContributionsofSelectGenomicCompartmentsandCellTypestoGeneticRiskforCoronaryArteryDiseasePMID:26509271
PRSLocation
Increased”association”withinregulatoryregionslinkedwithgeneexpression
Agene-basedassociationmethodformappingtraitsusingreferencetranscriptomedata PMID:26258848
Estimationofgeneexpressionalterationstartingfromgenotypedata
l Reducemultipletestburden(from105/106 variantsto103/104 genes)
l Simplifiedmeta-analysisofgene-basedresults
l Multipletissuescanbeevaluatedusingareferencetranscriptomedataset
Heritabilityandprediction
A comprehensive simulation study onclassification of RNA-Seq data 28832679
Multiclass cancer classification based on gene expression comparison.24918456
MachinelearningclassifierstartingfromimputedgeneexpressionDifferentlyfromgeneticvariantsdata,quantitativegene“score”
canbemoreeasilyintegratedinmachinelearningpipeline